Exonic Deletions in AUTS2 Cause a Syndromic Form of Intellectual Disability and Suggest a Critical Role for the C Terminus

被引：136

作者：

Beunders, Gea ^{[1
]}

Voorhoeve, Els ^{[1
]}

Golzio, Christelle ^{[2
]}

Pardo, Luba M. ^{[1
]}

Rosenfeld, Jill A. ^{[3
]}

Talkowski, Michael E. ^{[4
,5
,6
]}

Simonic, Ingrid ^{[7
]}

Lionel, Anath C. ^{[8
,9
,10
,11
]}

Vergult, Sarah ^{[12
]}

Pyatt, Robert E. ^{[13
,14
]}

van de Kamp, Jiddeke ^{[1
]}

Nieuwint, Aggie ^{[1
]}

Weiss, Marjan M. ^{[1
]}

Rizzu, Patrizia ^{[1
]}

Verwer, Lucilla E. N. I. ^{[1
]}

van Spaendonk, Rosalina M. L. ^{[1
]}

Shen, Yiping ^{[4
,5
,15
,16
]}

Wu, Bai-lin ^{[15
,17
,18
]}

Yu, Tingting ^{[15
,16
]}

Yu, Yongguo ^{[16
]}

Chiang, Colby ^{[4
,5
]}

Gusella, James F. ^{[4
,5
,6
]}

Lindgren, Amelia M. ^{[19
,20
]}

Morton, Cynthia C. ^{[6
,19
,20
]}

van Binsbergen, Ellen ^{[21
]}

Bulk, Saskia ^{[21
]}

van Rossem, Els ^{[22
]}

Vanakker, Olivier ^{[12
]}

Armstrong, Ruth ^{[7
]}

Park, Soo-Mi ^{[7
]}

Greenhalgh, Lynn ^{[23
]}

Maye, Una ^{[23
]}

Neill, Nicholas J. ^{[3
]}

Abbott, Kristin M. ^{[7
]}

Sell, Susan ^{[24
]}

Ladda, Roger ^{[24
]}

Farber, Darren M. ^{[25
]}

Bader, Patricia I. ^{[26
]}

Cushing, Tom ^{[27
]}

Drautz, Joanne M. ^{[27
]}

Konczal, Laura ^{[28
]}

Nash, Patricia ^{[29
]}

de Los Reyes, Emily ^{[30
]}

Carter, Melissa T. ^{[31
]}

Hopkins, Elizabeth ^{[32
]}

Marshall, Christian R. ^{[8
,9
,10
,11
]}

Osborne, Lucy R. ^{[33
,34
]}

Gripp, Karen W. ^{[32
]}

Thrush, Devon Lamb ^{[13
,35
]}

Hashimoto, Sayaka ^{[13
]}

机构：

[1] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, NL-1007 MB Amsterdam, Netherlands

[2] Duke Univ, Med Ctr, Dept Cell Biol, Ctr Human Dis Modeling, Durham, NC 27710 USA

[3] Perkin Elmer, Signature Genom Labs, Spokane, WA 99207 USA

[4] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res,Dept Genet, Boston, MA 02114 USA

[5] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res,Dept Neurol, Boston, MA 02114 USA

[6] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA

[7] Natl Hlth Serv Fdn Trust, Cambridge Univ Hosp, Addenbrookes Hosp, E Anglian Med Genet Serv, Cambridge CB2 0QQ, England

[8] Hosp Sick Children, Ctr Appl Genom, Toronto, ON M5G 1L7, Canada

[9] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1L7, Canada

[10] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada

[11] Univ Toronto, McLaughlin Ctr, Toronto, ON M5S 1A1, Canada

[12] Univ Hosp Ghent, Ctr Med Genet, B-9000 Ghent, Belgium

[13] Nationwide Childrens Hosp, Columbus, OH 43205 USA

[14] Ohio State Univ, Dept Pathol, Columbus, OH 43210 USA

[15] Boston Childrens Hosp, Dept Lab Med, Boston, MA 02114 USA

[16] Shanghai Jiao Tong Univ, Sch Med, Shanghai Childrens Med Ctr, Shanghai 200025, Peoples R China

[17] Fudan Univ, Childrens Hosp, Shanghai 200032, Peoples R China

[18] Fudan Univ, Inst Biomed Sci, Shanghai 200032, Peoples R China

[19] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[20] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA

[21] Univ Med Ctr Utrecht, Dept Med Genet, NL-3508 AB Utrecht, Netherlands

[22] Onze Lieve Vrouwe Ziekenhuis, B-9300 Aalst, Belgium

[23] Royal Liverpool Childrens Hosp, Liverpool L12 2AP, Merseyside, England

[24] Penn State Milton S Hershey Med Ctr, Hershey, PA 17033 USA

[25] Univ Louisville, Dept Neurol, Louisville, KY 40222 USA

[26] NE Indiana Genet Counseling Ctr, Ft Wayne, IN 46804 USA

[27] Univ New Mexico, Dept Pediat, Pediat Genet Div, Albuquerque, NM 87131 USA

[28] Case Western Reserve Univ, Univ Hosp, Cleveland, OH 44106 USA

[29] Nationwide Childrens Hosp, Dept Behav Pediat, Columbus, OH 43205 USA

[30] Ohio State Univ, Dept Pediat & Neurol, Columbus, OH 43210 USA

[31] Hosp Sick Children, Div Clin & Metab Genet, Toronto, ON M5G 1X8, Canada

[32] Alfred I duPont Hosp Children, Div Med Genet, Wilmington, DE 19803 USA

[33] Univ Toronto, Dept Med, Toronto, ON M5S 1A8, Canada

[34] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada

[35] Ohio State Univ, Dept Pediat, Columbus, OH 43210 USA

[36] Vrije Univ Amsterdam Med Ctr, Dept Pathol, NL-1007 MB Amsterdam, Netherlands

[37] Vrije Univ Amsterdam, Ctr Neurogenom & Cognit Res, Dept Funct Genom, NL-1081 HV Amsterdam, Netherlands

[38] Erasmus Univ, Dept Child & Adolescent Psychiat, NL-3000 CB Rotterdam, Netherlands

[39] Univ Antwerp, Dept Med Genet, B-2650 Edegem, Belgium

[40] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[41] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA

[42] Penn State Univ, Dept Biochem & Mol Biol, Dept Anthropol, University Pk, PA 16803 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2013年 / 92卷 / 02期

基金：

美国国家卫生研究院; 英国惠康基金;

关键词：

TRANSLOCATION BREAKPOINT; MUTATIONS; AUTISM; ABNORMALITIES; GENERATION; PHENOTYPE; DATABASE; GENES;

D O I：

10.1016/j.ajhg.2012.12.011

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3' AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future.

引用

页码：210 / 220

页数：11

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